The present invention relates to a series of perhydrothiazepine and perhydroazepine derivatives which have the valuable ability to lower blood pressure and hence which are of potential use in the treatment of humans and other animals suffering from elevated blood pressure.
There is considerable evidence that reduction of elevated blood pressure reduces the risks of morbidity and mortality. Elevated blood pressure (hypertension) can be caused by a variety of factors and a large number of drugs is available for the treatment of hypertension, the drug of choice being dictated in large measure by the cause of the hypertension, as well as the degree of hypertension and the acceptance of the treatment by the patient. One of the known causes of hypertension is the presence in blood plasma of the polypeptide known as angiotension II, and a reduction in the blood plasma levels of angiotensin II has been shown to reduce hypertension. The first step in the production of angiotensin II in the mammalian body is the conversion of a blood protein, by the enzyme renin, to a polypeptide known as "angiotensin I". This angiotensin I is then converted by angiotensin converting enzyme (hereinafter referred to, as is conventional, as "ACE") to angiotensin II. The enzyme ACE has another metabolic function, namely it participates in the metabolism of bradykinin, a natural vasodilator, converting it to an inactive metabolite.
Hence, the enzyme ACE is capable of raising blood pressure by two routes: one is the production of angiotensin II, which itself directly raises blood pressure; the second is the inactivation of bradykinin which, through its vasodilatory activity, tends to reduce blood pressure. There has, therefore, been considerable interest in recent years in the development of compounds having the ability to inhibit the activity of ACE.
For example, certain perhydro-1,4-thiazepin-5-one derivatives are disclosed in U.S. patent application Ser. No. 721 303, filed 9 Apr. 1985 which issued as U.S. Pat. No. 4,699,905; these thiazepine derivatives differ from those of the present invention principally in the nature of the substituent at the 6-position. Also, certain perhydroazepin-2-one derivatives are disclosed in U.S. patent application Ser. No. 917 041, filed 9 Oct. 1986; these azepine derivatives also differ from those of the present invention principally in the nature of the substituent at the 3-position.
Other close prior art relevant to the azepine derivatives of the present invention is European Patent Publication No. 46 291, which discloses a series of perhydroazepin-2-one (or caprolactam) derivatives having substituents at the 1- and 3-positions and optionally also having a substituent at the 7-position. The compounds of European Patent Publication No. 46 291, however, unlike the compounds of the present invention, are unsubstituted at the 6-position. Surprisingly, we have found that the compounds of the present invention have several advantages over the prior art compounds of European Patent Publication No. 46 291, including a higher ACE inhibitory activity and a longer duration of this activity in vivo.
There is also a mention of certain 1,4-thiazepine derivatives similar to those of the present invention in European Patent Publication No. 156 455, but the 1,4-thiazepine derivatives disclosed therein differ from those of the present invention in that they have a benzene ring fused to the thiazepine ring at the 2- and 3-positions
The compounds of the present invention have the advantages over the prior art compounds of higher activity and a longer duration of activity, in general than the prior art compounds, even, in some cases greater than that of U.S. patent application Ser. No. 721 303. Moreover, they are believed to be potentially more useful for oral administration, which, is well known, is normally the preferred route of administration for this type of drug.